There is cumulative evidence for multidirectional differentiation in lung carcinomas. Based on in vitro studies on the biology of small cell carcinoma of the lung (SCLC) good markers for this tumor type have been established. Accordingly, we investigated the occurrence of relevant neuroendocrine NE markers in 120 newly diagnosed lung cancers of major histological types by immunocytochemistry. We examined paraffin sections using avidin-biotin immunoperoxidase method with monoclonal and/or polyclonal antibodies to chromogranin A (a structural protein in endocrine granules), Leu-7 (HNK-1, an antigen shared by neurons, endocrine cells and their tumors with human natural killer cells), neuron specific enolase, the amine serotonin, and the polypeptide hormones bombesin, adrenocorticotropin, calcitonin and neurotensin. From the results we can conclude that 1) most, but not all, SCLC and carcinoids express multiple (more than 3) NE markers in a high percentage of tumor cells; 2) occassional non small cell lung cancers (NSCLC) show staining patterns indistinguishable from SCLC; 3) many NSCLC contain a small subpopulation of cells expressing NE markers. The same panel of markers will now be prospectively used to study the tumor tissues from patients in SCLC and non small cell lung cancer protocols, and the results correlated with their prognosis and response to theraby. The patients who have non small cell lung cancer with multiple NE markers may benefit from SCLC -like treatment protocol. It is apparent that the c-myc and myc related sequences such as N-myc and the newly discovered L-myc genes may play a role in the clinical and cellular biology of human SCLC. To further study the relationship of oncogene amplification and expression to tumor progression and morphology we are in a process to establish in situ hybridization techniques using various myc related DNA probes in our laboratory. this will be the major research effort during the coming year of Dr. Jiang Gu, who has recently joined our staff as a Fogarty Fellow.